The role of insulin dissociation from its endosomal receptor in insulin degradation

Bevan, A. Paul; Seabright, Paul J.; Tikerpae, J.; Posner, Barry I.; Smith, Geoffrey D.; Siddle, Kenneth

doi:10.1016/s0303-7207(00)00224-0

Cited by 9 publications

(7 citation statements)

References 57 publications

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“…Furthermore, the low internalization rate of HMR 1964 correlated with a marginal activation of ERK-1/2 by this analog that was even lower than that induced by insulin. It has also been demonstrated that sustained receptor binding decreases endosomal insulin degradation, resulting in enhanced signaling from this intracellular compartment (36). This would explain the strong activation of MAPK by Asp B10 insulin, as this analog exhibits a moderate internalization combined with a very low degradation (Table 1).…”

Section: Discussionmentioning

confidence: 96%

A Novel Insulin Analog With Unique Properties

et al. 2003

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The potentially enhanced mitogenic activity of insulin analogs represents a safety risk that requires detailed analysis of new analogs considered for therapeutic applications. We assessed the signaling properties and mitogenic potency of two novel rapid-acting insulin analogs, Lys Insulin therapy of diabetic patients aims to achieve tight blood glucose control to reduce the progression of long-term complications (1). However, the pharmacokinetic characteristics of currently available insulin preparations are unable to mimic the pattern of endogenous insulin secretion and make it impossible to achieve sustained normoglycemia (2). Great efforts have been made to develop novel insulin molecules with altered pharmacodynamic characteristics that might lead to improved glycemic control using recombinant DNA technology (rev. in 3-5). One limiting factor is the slow absorption of conventional unmodified insulin from subcutaneous tissues because of the slow dissociation rate of hexameric insulin complexes into monomers at the injection site (6,7). Modification of the B26ϪB30 region of the insulin molecule, particularly substitution of amino acids with charged residues at the association sites, allows the production of a range of insulin analogs with reduced selfassociation that exhibit no profound perturbations of insulin receptor recognition (4,8). This has been demonstrated for insulin analogs such as Lispro (Lys B28 ,Pro B29 ) insulin and insulin aspart (Asp B28 insulin), two rapidacting insulins that are in clinical use and improve postprandial glycemic control (3,5).A major concern related to the long-term use of insulin analogs stems from the observation that modification of the insulin molecule in the B10 and B26ϪB30 regions alters the affinity for the IGF-I receptor more than for the insulin receptor and may lead to enhanced mitogenic activity of these analogs (9). This potential safety risk was first recognized for the analog Asp B10 insulin, which was found to exhibit a tumor-promoting activity in SD rats (10) and to induce a profound mitogenic effect in many cell systems (11-13). The enhanced mitogenic signaling profile of an insulin analog may result from 1) an increased affinity toward the IGF-I receptor, resulting in augmented IGF-I receptor signaling (9); 2) the so-called time-dependent specificity that describes a distinct correlation between the mitogenic potential and the occupancy time at the insulin receptor for a given insulin analog (14); and 3) a combination of both IGF-I and insulin receptorϪ mediated processes. Most recent data suggest that the mitogenic properties correlate better with the IGF-I recep-

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Section: Discussionmentioning

confidence: 96%

A Novel Insulin Analog With Unique Properties

et al. 2003

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“…21,40 The dephosphorylation site may be where PTPases are docked, 25,40 or simply the point in the endosomal trafficking cycle where a sufficient conformational change occurs, perhaps secondary to the loss of insulin from the IR, where endosomal associated PTPase(s) may be able to complete dephosphorylation of the IR. In support of this latter hypothesis, Bevan et al 13 found that promotion of sustained receptor binding decreases endosomal insulin degradation and extends the half-life of the activated endosomal receptor. Contreres et al 17 found that the acidic pH of endosomes fosters a conformation-dependent inactivation of the IR kinase (IRK), and an acidic endosomal insulinase has recently been identified as cathespin D. 2 An understanding of the molecular mechanisms that influence rate-limiting step k 43 may lead to treatments which could result in its prolongation, possibly increasing insulin sensitivity and improving the condition of insulin resistance in diabetic patients.…”

Section: Figure 7 Using the Six-pool Model To Simulate Cell-associatmentioning

confidence: 90%

“…13 We assume this range for the late endosomal pools x 4 and x 7 ; thus, k 64 ≈ k 57 , and k 43 represents the rate at which the phosphorylated IR traverses the plasma membrane and travels through the cytosol to its site of dephosphosphorylation. The six-pool model equations for saturating conditions are u = 100 nM insulin …”

Section: Six-pool Model At 100 Nm Insulinmentioning

confidence: 99%

“…36 The tyrosine-phosphorylated IR is then internalized via endosomes. The endosomal acidic environment (pH ∼6) promotes ligand-receptor dissociation, 13 as well as a conformational dependent inactivation of the IR. 17 Insulin is degraded within the endosome by an acidic insulinase, 2,19 and the IR is either sent to lysosomes for degradation or recycled to the plasma membrane for another round of binding, activation, and internalization.…”

Section: Introductionmentioning

confidence: 99%

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Role of Endosomal Trafficking Dynamics on the Regulation of Hepatic Insulin Receptor Activity: Models for Fao Cells

2006

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Evidence indicates that endosomal insulin receptor (IR) trafficking plays a role in regulating insulin signal transduction. To evaluate its importance, we developed a series of biokinetic models for quantifying activated surface and endosomal IR dynamics from published experimental data. Starting with a published two-compartment Fao hepatoma model, a four-pool model was formulated that depicts IR autophosphorylation after receptor binding, IR endosomal internalization/trafficking, insulin dissociation from and dephosphorylation of internalized IR, and recycling of unliganded, dephosphorylated IR to the plasma membrane. Quantification required three additional data sets, two measured, but unmodeled by the same group. A five-pool model created to include endosomal trafficking of the nonphosphorylated insulin-IR complex was fitted using the same data sets, augmented with another published data set. Creation of a six-pool model added the physiologically relevant dissociation of insulin ligand from the activated endosomal IR. More importantly, all three models, validated against additional data not used in model fitting, predict that, mechanistically, internalization of activated IR is a rate-limiting step, at least under the receptor saturating conditions of the fitting data. This rate includes the transit time to a site where insulin dissociation from and/or dephosphorylation of the IR occurs by docking with protein-tyrosine phosphatases (PTPases), or where a sufficient conformational change occurs in the IR, perhaps due to insulin-IR dissociation, where associated PTPases may complete IR dephosphorylation. Our new models indicate that key events in endosomal IR trafficking have significance in mediating IR activity, possibly serving to regulate insulin signal transduction.

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“…An acute increase in insulin exposure of cells therefore leads to a dose-dependent temporary loss of insulin receptors on the plasma membrane [ 47 , 48 ]. Insulin degradation in endosomes is primarily responsible for the dissociation of insulin from the insulin receptor; although, intact insulin is also released from receptors, and the rate of release of insulin from the receptor (via simple dissociation or degradation) is the key determinant of the rate of receptor recycling back to the plasma membrane [ 41 , 49 , 50 , 51 , 52 ]. In addition, the insulin–insulin receptor interaction itself depends on the dose and duration of exposure to insulin.…”

Section: Introductionmentioning

confidence: 99%

Insulin Clearance in Obesity and Type 2 Diabetes

Koh

Cao

Mittendorfer

2022

IJMS

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Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.

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The role of insulin dissociation from its endosomal receptor in insulin degradation

Cited by 9 publications

References 57 publications

A Novel Insulin Analog With Unique Properties

A Novel Insulin Analog With Unique Properties

Role of Endosomal Trafficking Dynamics on the Regulation of Hepatic Insulin Receptor Activity: Models for Fao Cells

Insulin Clearance in Obesity and Type 2 Diabetes

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